Pharmaceutical dosage forms of biguanide-sulfonylurea combinations

ABSTRACT

The present invention relates to orally administered pharmaceutical compositions that include a combination of antidiabetic agents wherein one agent is present in an extended release form and the other agent is present in an immediate release form. For example, in one embodiment the dosage form includes an extended release layer that includes a biguanide; and an immediate release layer that includes a sulfonylurea.

FIELD OF THE INVENTION

The present invention relates to orally administered pharmaceuticalcompositions that include a combination of antidiabetic agents whereinone agent is present in an extended release form and the other agent ispresent in an immediate release form.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a term generally used to refer to variouspathological states characterized by hyperglycemia and alteredmetabolism of lipids, carbohydrates and proteins. These conditions alsoare often associated with other co-morbidities, such as obesity and anincreased risk of cardiovascular disease.

Diabetic conditions are generally classified as either insulin-dependentdiabetes mellitus (IDDM, Type I diabetes) or non-insulin-dependentdiabetes mellitus (NIDDM, Type II diabetes).

Virtually all forms of diabetes are due to a decrease in the circulatingconcentration of insulin (insulin deficiency) and/or a decrease in theresponse of peripheral tissues to insulin (insulin resistance). Theseabnormalities lead to alterations in the metabolism of carbohydrates,lipids, ketones and amino acids, and a hyperglycemic condition. IDDMappears to have an autoimmune etiology that results in destruction of Bislet cells in the pancreas and leads to an inability to produceinsulin. The etiology of NIDDM, the most prevalent form of diabetes, ismore complex and possibly heterogeneous. NIDDM patients generally have aloss of B-cell volume, decreased circulating levels of insulin, andinsulin resistance.

A variety of antidiabetic compounds are known. For example,sulfonylureas are a group of drugs that induce hypoglycemia bystimulating insulin release from the pancreas. Suitable sulfonyl ureasinclude acetohexamide, glibenclamide (glyburide), glipizide, gliclazide,glimepiride, tolazamide and tolbutamide. Prior to 1995, sulfonyl ureaswere the most widely utilized antidiabetics for the treatment of NIDDM.These act by augmenting insulin secretion from the beta cells in thepancreas. Glyburide is available as tablets of 1.25 mg, 2.5 mg, and 5 mgstrengths for oral administration and is administered twice a day.Glipizide tablets are available in 5 mg and 10 mg tablets. Similarly,glimperide is available in 1 mg, 2 mg, and 4 mg tablets and isadministered once daily.

Biguanides are another group of drugs which were first introduced in themid 1950's and have shown efficacy in the treatment of hyperglycemia.The best-known agents of this type include metformin, phenformin andbuformin, with metformin being the most well known compound of thisclass. Metformin has been widely prescribed for lowering blood glucosein patients with NIDDM, is marketed as Glucophage tablets containing 500mg, 850 mg, or 1000 mg of metformin hydrochloride and has a maximumrecommended dose of 2550 mg per day. However, being a short acting drug,metformin requires twice-daily or three-times-a-day dosing (500-850 mgtab 2-3×/day or 1000 mg bid with meals). Unlike the sulfonylureas,biguanides do not induce release of insulin from the pancreas. It isthought that its effects are mediated by increasing insulin activity inperipheral tissues, reducing hepatic glucose output due to inhibition ofgluconeogenesis, and reducing the absorption of glucose from theintestine.

These agents are often given in combination with drugs that increase theoutput of insulin from the pancreas, such as the sulfonylureas. Thiscombination sometimes results in greater efficacy, the ability to uselower doses of the drugs, and reduced adverse side effect profile.Adverse events associated with the administration of biguanides includeanorexia, nausea, vomiting and diarrhea. The adverse events may bepartially avoided by either reducing the initial and/or maintenance doseusing an extended-release dosage form. Another advantage of anextended-release dosage form is a reduction in the frequency ofadministration. Findings suggest that extended-release dosage form of abiguanide may improve the quality of therapy in patients with NIDDM.

Studies have shown that a combination of insulin secretion enhancers andinsulin sensitivity enhancers has a remarkable effect on glycemiccontrol. The different mechanisms of action in targeting hyperglycemiaare complimentary and capable of providing a remedy for both thedeficiency in insulin secretion and insulin sensitivity conditions. Thecombination therapy therefore plays an important therapeutic rolebecause it provides an effective metabolic control in NIDDM patients inwhom therapy with only sulfonylureas or only biguanides becomesineffective with time.

The use of combinations of metformin (a biguanide) and glyburide (asulfonylurea) has been demonstrated to be synergistic in clinical trialswhen compared with the use of the individual agents separately (seePhysician's Desk Reference 2000, page 832). The monograph also disclosesthe use of combinations of metformin and sulfonylureas for patients notcontrolled on metformin alone. Several references pertain topharmaceutical compositions having combinations of biguanides andsulfonylureas providing for controlled or immediate release of both ofthe drugs. For example, a unit-dose combination of metformin andglipizide as an immediate release formulation is commercially available(Zidmin™ tablets, Wockhardt), and a combination dosage form of metforminand glyburide for immediate release is described in U.S. Pat. No.6,303,146 to Bonhomme et al.

Extended release tablets that employ either a biguanide alone or asulfonylurea drug alone have been described in the prior art. Forexample, WO 96/08243 discloses a controlled release dosage form thatcontains only metformin hydrochloride as the active ingredient, andemploys a hydrogel to push the active ingredient from the dosage form.Similarly, U.S. Pat. Nos. 5,545,413; 5,591,454; and 5,091,190 disclosecontrolled release dosage forms that contain only the drug glipizide,and employ a hydrogel to push the active ingredient from the dosageform.

U.S. Pat. Nos. 6,099,862 and 6,284,275, both to Chen et al., describe acombination composition for the simultaneous controlled release of abiguanide and a sulfonylurea. The composition comprises a corecontaining the two active agents along with other excipients and asemipermeable controlled release coating from which the release of theactive agents is controlled by the presence of at least one passagewayin the coat.

Although combinations of two antidiabetic agents are well known in theart and are convenient to formulate, a combination providing extendedrelease of a water-soluble active, i.e., a biguanide, and immediaterelease of a water-insoluble or sparingly soluble active, i.e.,sulfonylurea, is difficult to achieve using a simple and cost-effectiveprocess.

SUMMARY OF THE INVENTION

In one general aspect there is provided a solid pharmaceutical dosageform for oral administration. The dosage form includes an extendedrelease layer that includes a biguanide; and an immediate release layerthat includes a sulfonylurea.

Embodiments of the dosage form may include one or more of the followingfeatures. For example, the biguanide may be one or more of metformin,phenformin, and buformin and, in particular, metformin. The sulfonylureamay be one or more of glipizide, glimepiride, glibornuride, glyburide,glisoxepide, gliclazide, acetohexamide, chlorpropamide, tolazamide andtolbutamide and, in particular, glimepiride.

After oral administration, the biguanide may be released over a periodof about 4 hours to about 36 hours and, more particularly, over a periodof about 8 to about 24 hours.

The dosage form may be tablets or capsules. The tablet may include acoating. The capsules may include one or more of pellets, beads,granules, multiparticulates, tablets and powder.

The extended release layer may be a matrix and the matrix may be auniform mixture of the biguanide and one or more rate controllingpolymers. The one or more rate-controlling polymers may be hydrophilicpolymers, hydrophobic polymers, or a combination thereof. The matrix mayfurther include one or more pharmaceutically acceptable excipients. Thepharmaceutically acceptable excipients may be one or more of diluents,lubricants, disintegrants, binders, glidants, coloring agents, andflavoring agents.

The biguanide may be layered onto a pharmaceutically inert core or seed.The inert core or seed may be hydrosoluble or hydroinsoluble.

The immediate release outer layer may further include film-formingpolymers and optionally other pharmaceutically acceptable excipients.The film-forming polymers may be water-soluble polymers. Thepharmaceutically acceptable excipients may be one or more ofplasticizers, opacifiers and colorants.

The dosage form may further include one or more of glitazones, insulin,alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalenesynthesis inhibitors and angiotensin-converting enzyme inhibitors.

The dosage form may further include a wetting agent in the immediaterelease layer and the immediate release layer may include a sulfonylureaand the wetting agent in a weight ratio ranging from about 10:1 to about1:25. The wetting agent may be one or more of hydrophilic andhydrophobic surfactants. The hydrophilic surfactant may be one or moreof non-ionic surfactants, ionic surfactants or mixtures thereof. Thehydrophobic surfactants may be one or more of alcohols; polyoxyethylenealkylethers; fatty acids; glycerol fatty acid monoesters; glycerol fattyacid diesters; acetylated glycerol fatty acid monoesters; acetylatedglycerol fatty acid diesters, lower alcohol fatty acid esters;polyethylene glycol fatty acid esters; polyethylene glycol glycerolfatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of monoglycerides;lactic acid derivatives of diglycerides; propylene glycol diglycerides;sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers, polyethyleneglycolsas esters or ethers, polyethoxylated castor oil; polyethoxylatedhydrogenated castor oil, polyethoxylated fatty acid from castor oil orpolyethoxylated fatty acid from castor oil or polyethoxylated fatty acidfrom hydrogenated castor oil.

The non-ionic surfactants may be one or more of alkylglucosides;alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;caprylocaproyl macrogolglycerides, polyoxyethylene alkyl ethers;polyoxyethylene alkylphenols; polyethylene glycol fatty acid esters;polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitanfatty acid esters; polyoxyethylene-polyoxypropylene block copolymers;polyglycerol fatty acid esters; polyoxyethylene glycerides;polyoxyethylene sterols, derivatives, and analogues thereof;polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetableoils; reaction products of polyols and at least one member of the groupconsisting of fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols; sugar esters, sugar ethers;sucroglycerides; and mixtures thereof.

The ionic surfactants may be one or more of alkyl ammonium salts; bileacids and salts, analogues, and derivatives thereof; fatty acidderivatives of amino acids, oligopeptides, and polypeptides; glyceridederivatives of amino acids, oligopeptides, and polypeptides; acyllactylates; monoacetylated tartaric acid esters of monoglycerides,monoacetylated tartaric acid esters of diglycerides, diacetylatedtartaric acid esters of monoglycerides, diacetylated tartaric acidesters of diglycerides; succinylated monoglycerides; citric acid estersof monoglycerides; citric acid esters of diglycerides; alginate salts;propylene glycol alginate; lecithins and hydrogenated lecithins;lysolecithin and hydrogenated lysolecithins; lysophospholipids andderivatives thereof; phospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; and mixturesthereof.

The extended release layer may be a core and the immediate release layercovers at least a portion of the core. The dosage form may be abilayered dosage form.

In another general aspect there is provided a process for preparing asolid, orally administered pharmaceutical dosage form of an extendedrelease core of a biguanide and an immediate release layer of asulfonylurea. The process includes (a) dispersing the biguanide in asolid matrix to form a core having a surface; and (b) layering theimmediate release layer of the sulfonylurea on the surface of the core.

Embodiments of the process may include one or more of the followingfeatures. For example, layering the immediate release layer may furtherinclude layering one or more wetting agents. The sulfonylurea and theone or more wetting agents may be present in the immediate release layerin a weight ratio ranging from about 10:1 to about 1:25. The one or morewetting agents may be one or both of hydrophilic and hydrophobicsurfactants. The hydrophilic surfactants may be one or more of non-ionicsurfactants, ionic surfactants and mixtures thereof.

The hydrophobic surfactants may be one or more of alcohols;polyoxyethylene alkylethers; fatty acids; glycerol fatty acidmonoesters; glycerol fatty acid diesters; acetylated glycerol fatty acidmonoesters; acetylated glycerol fatty acid diesters, lower alcohol fattyacid esters; polyethylene glycol fatty acid esters; polyethylene glycolglycerol fatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of monoglycerides;lactic acid derivatives of diglycerides; propylene glycol diglycerides;sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers, polyethyleneglycolsas esters or ethers, polyethoxylated castor oil; polyethoxylatedhydrogenated castor oil, polyethoxylated fatty acid from castor oil orpolyethoxylated fatty acid from castor oil or polyethoxylated fatty acidfrom hydrogenated castor oil.

The non-ionic surfactants may be one or more of alkylglucosides;alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;caprylocaproyl macrogolglycerides, polyoxyethylene alkyl ethers;polyoxyethylene alkylphenols; polyethylene glycol fatty acid esters;polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitanfatty acid esters; polyoxyethylene-polyoxypropylene block copolymers;polyglycerol fatty acid esters; polyoxyethylene glycerides;polyoxyethylene sterols, derivatives, and analogues thereof;polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetableoils; reaction products of polyols and at least one member of the groupconsisting of fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols; sugar esters, sugar ethers;sucroglycerides; and mixtures thereof.

The ionic surfactants may be one or more of alkyl ammonium salts; bileacids and salts, analogues, and derivatives thereof; fatty acidderivatives of amino acids, oligopeptides, and polypeptides; glyceridederivatives of amino acids, oligopeptides, and polypeptides; acyllactylates; monoacetylated tartaric acid esters of monoglycerides,monoacetylated tartaric acid esters of diglycerides, diacetylatedtartaric acid esters of monoglycerides, diacetylated tartaric acidesters of diglycerides; succinylated monoglycerides; citric acid estersof monoglycerides; citric acid esters of diglycerides; alginate salts;propylene glycol alginate; lecithins and hydrogenated lecithins;lysolecithin and hydrogenated lysolecithins; lysophospholipids andderivatives thereof; phospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; and mixturesthereof.

The biguanide may be one or more of metformin, phenformin and buforminand, in particular, may be metformin. The sulfonylurea may be one ormore of glipizide, glimepiride, glibornuride, glyburide, glisoxepide,gliclazide, acetohexamide, chlorpropamide, tolazamide and tolbutamideand, in particular, may be glimepiride.

After oral administration of the dosage form, the biguanide is releasedover a period of about 4 to about 36 hours and, in particular over aperiod of about 8 to about 24 hours.

The process may further include forming a tablet or a capsule and maystill further include coating the tablet. The capsule may contain one ormore of pellets, beads, granules, multiparticulates, tablets and powder.

The core may be a matrix. The matrix may further include a uniformmixture of the biguanide and one or more rate controlling polymers. Theone or more rate-controlling polymers may be one or both of hydrophilicand hydrophobic polymers. The matrix may further include one or morepharmaceutically acceptable excipients. The pharmaceutically acceptableexcipients may be one or more of diluents, lubricants, disintegrants,binders, glidants, colorants, and flavorants.

The biguanide may be layered onto pharmaceutically inert core or seeds.The inert core or seeds may be hydrosoluble or hydroinsoluble.

The immediate release layer may further include film-forming polymersand optionally other pharmaceutically acceptable excipients. Thefilm-forming polymers may be water-soluble polymers. Thepharmaceutically acceptable excipients may be one or more ofplasticizers, opacifiers and colorants.

The process may further include placing a seal-coat over the core,wherein the seal-coat includes hydrophilic polymers.

In another general aspect there is provided a process for preparing abilayered, solid, orally administered pharmaceutical dosage form of abiguanide and a sulfonylurea. The process includes (a) dispersing thebiguanide in an extended release carrier base material; (b) separatelydispersing the sulfonylurea in an immediate release carrier basematerial; and (c) compressing the materials of step a and step b to formthe bilayered dosage form.

Embodiments of the process may include one or more of the followingfeatures. For example, the immediate release carrier base material mayfurther include one or more wetting agents before or after dispersingthe sulfonylurea. The sulfonylurea and the one or more wetting agentsmay be present in a weight ratio ranging from about 10:1 to about 1:25.The one or more wetting agents may be one or both of hydrophilic andhydrophobic surfactants. The hydrophilic surfactants may be one or moreof non-ionic surfactants, ionic surfactants or mixtures thereof.

The hydrophobic surfactants may be one or more of alcohols;polyoxyethylene alkylethers; fatty acids; glycerol fatty acidmonoesters; glycerol fatty acid diesters; acetylated glycerol fatty acidmonoesters; acetylated glycerol fatty acid diesters, lower alcohol fattyacid esters; polyethylene glycol fatty acid esters; polyethylene glycolglycerol fatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of monoglycerides;lactic acid derivatives of diglycerides; propylene glycol diglycerides;sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers, polyethyleneglycolsas esters or ethers, polyethoxylated castor oil; polyethoxylatedhydrogenated castor oil, polyethoxylated fatty acid from castor oil orpolyethoxylated fatty acid from castor oil or polyethoxylated fatty acidfrom hydrogenated castor oil.

The non-ionic surfactants may be one or more of alkylglucosides;alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;caprylocaproyl macrogolglycerides, polyoxyethylene alkyl ethers;polyoxyethylene alkylphenols; polyethylene glycol fatty acid esters;polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitanfatty acid esters; polyoxyethylene-polyoxypropylene block copolymers;polyglycerol fatty acid esters; polyoxyethylene glycerides;polyoxyethylene sterols, derivatives, and analogues thereof;polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetableoils; reaction products of polyols and at least one member of the groupconsisting of fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols; sugar esters, sugar ethers;sucroglycerides; and mixtures thereof.

The ionic surfactants may be one or more of alkyl ammonium salts; bileacids and salts, analogues, and derivatives thereof; fatty acidderivatives of amino acids, oligopeptides, and polypeptides; glyceridederivatives of amino acids, oligopeptides, and polypeptides; acyllactylates; monoacetylated tartaric acid esters of monoglycerides,monoacetylated tartaric acid esters of diglycerides, diacetylatedtartaric acid esters of monoglycerides, diacetylated tartaric acidesters of diglycerides; succinylated monoglycerides; citric acid estersof monoglycerides; citric acid esters of diglycerides; alginate salts;propylene glycol alginate; lecithins and hydrogenated lecithins;lysolecithin and hydrogenated lysolecithins; lysophospholipids andderivatives thereof; phospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; and mixturesthereof.

The biguanide may be selected from one or more of metformin, phenforminand buformin and, in particular, may be metformin. The sulfonylurea maybe selected from one or more of glipizide, glimepiride, glibornuride,glyburide, glisoxepide, gliclazide, acetohexamide, chlorpropamide,tolazamide and tolbutamide and, in particular, may be gllimepiride.

After oral administration of the dosage form, the biguanide may bereleased over a period of about 4 to about 36 hours and, in particular,over a period of about 8 to about 24 hours.

The process may further include forming a tablet or a capsule and maystill further include coating the tablet. The capsule may contain one ormore of pellets, beads, granules, multiparticulates, tablets and powder.

The biguanide layer may be a matrix and the matrix may include a uniformmixture of the biguanide and one or more rate controlling polymers. Theone or more rate-controlling polymers may be either or both ofhydrophilic and hydrophobic polymers. The matrix may further include oneor more pharmaceutically acceptable excipients. The pharmaceuticallyacceptable excipients may be one or more of diluents, lubricants,disintegrants, binders, glidants, colorants, and flavorants.

The biguanide may be layered onto pharmaceutically inert core or seeds.The inert core or seeds may be hydrosoluble or hydroinsoluble.

The immediate release carrier base material may further includefilm-forming polymers and optionally other pharmaceutically acceptableexcipients. The film-forming polymers may be water-soluble polymers. Thepharmaceutically acceptable excipients may be one or more ofplasticizers, opacifiers and colorants.

The process may further include providing a seal-coat of one or morehydrophilic polymers between the two layers.

In another general aspect there is provided a method of treatingnon-insulin dependent diabetes mellitus in a patient in need thereof.The method includes administering a solid, pharmaceutical dosage form ofthe combination of a biguanide and a sulfonylurea, wherein the dosageform provides extended-release of the biguanide and immediate release ofthe sulfonylurea.

Embodiments of the method may include one or more of the followingfeatures or any feature described above. For example, the biguanide maybe one or more of metformin, phenformin, and buformin and, inparticular, may be metformin. The sulfonylurea may be one or more ofglipizide, glimepiride, glibornuride, glyburide, glisoxepide,gliclazide, acetohexamide, chlorpropamide, tolazamide and tolbutamideand, in particular, may be glimepiride.

After oral administration of the dosage form, the biguanide may bereleased over a period of about 4 to about 36 hours and, in particular,over a period of about 8 to about 24 hours.

The dosage form may tablets or capsules and the dosage form may furtherinclude one or more of glitazones, insulin, alpha-glucosidaseinhibitors, meglitinides, fibrates, statins, squalene synthesisinhibitors and angiotensin-converting enzyme inhibitors.

The details of one or more embodiments of the inventions are set forthin the description below. Other features, objects and advantages of theinventions will be apparent from the description and claims.

DETAILED DESCRIPTION OF THE INVENTION

Hydrophobic therapeutic agents, i.e., therapeutic compounds having poorsolubility in aqueous solution, can be difficult to formulate in adosage form that provides effective administration of the therapeuticagent to patients. A well-designed formulation must, at a minimum, becapable of presenting a therapeutically effective amount of thehydrophobic compound to the desired absorption site, in an absorbableform. Even this minimal functionality is difficult to achieve whendelivery of the hydrophobic therapeutic agent requires interaction withaqueous physiological environments, such as gastric and intestinalfluids. Pharmaceutical compositions for delivery of such hydrophobictherapeutic agents must carry the hydrophobic compound through theaqueous environment, while maintaining the hydrophobic compound in anabsorbable form, and avoiding the use of physiologically harmfulsolvents or excipients.

A similar problem is faced in formulating extended release dosage formsfor highly soluble therapeutic agents. The high solubility of thetherapeutic agent requires the incorporation of a high percentage of arate-controlling polymer to achieve a desired release profile andprolonged effect. Further, it is difficult to control the initial burstof the drug from the formulation.

Therefore, there exists a need for pharmaceutical compositions for oraladministration that include a combination of a hydrophobic,water-insoluble therapeutic agent, i.e., a sulfonylurea, in an immediaterelease form and a highly water-soluble therapeutic agent, i.e., abiguanide, in an extended-release form that has the characteristics ofachieving an effect over twenty four hours after once dailyadministration.

The invention provides a dosage form containing both a sulfonylurea anda biguanide. The sulfonylurea is contained in an immediate-release formso that it is released substantially immediately upon ingestion (i.e.,upon swallowing). Generally, at least 80% of the sulfonylurea isreleased from the dosage form within an hour after administration. Thebiguanide, by contrast, is released in a sustained fashion—at leastabout 75% of the drug contained in the dosage form is released over aperiod of four to thirty six hours, preferably about eight to twentyfour hours. The term “about” as used above and elsewhere herein meansplus or minus 10% for each of the numerical limits.

The pharmaceutical compositions of the present invention can beadministered orally in the form of tablets, such as coated tablets orbilayered tablets, or in the form of capsules containing pellets, beads,granules, multiparticulates, tablets, or powder.

Biguanide, as used herein, is intended to include metformin, phenforminand buformin and their salts, solvates, hydrates, and polymorphs. Inparticular, the biguanide may be metformin. Different salts of metforminthat can be used include hydrochloride, acetate, maleate, fumarate,succinate, and other salts. The daily effective dose of metformin mayrange from about 500 mg to about 2550 mg and, in particular, the dosemay be a single dose of about 500 mg to about 1000 mg. The biguanide maybe present in an amount from about 40% to about 75% by weight of thetotal composition.

The biguanide may be incorporated in an extended release carrier base bydispersing in a rate-controlling polymer matrix, as described in ourpending application, which is published as WO 03/028704. Alternatively,the biguanide may be layered onto pharmaceutically acceptable inertcores or seeds in admixture with rate-controlling polymers or surroundedby rate-controlling polymers.

The term matrix, as used herein, refers to a uniform mixture of abiguanide, rate-controlling polymers and, optionally, other excipients.The rate-controlling polymers may be hydrophilic, hydrophobic or acombination thereof. The rate-controlling polymers are uniformlydispersed throughout the matrix to achieve uniform drug release.Hydrophilic polymers include cellulose derivatives such ashydroxypropylcellulose, hydroxypropyl methylcellulose,hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose or combinations thereof.The hydrophobic polymers may include one or more of poly (ethylene)oxide, ethyl cellulose, cellulose acetate, cellulose acetate butyrate,hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, andcopolymers of acrylic or methacrylic acid esters, waxes, shellac andhydrogenated vegetable oils.

In addition to the active and rate-controlling polymers, the matrix mayinclude other excipients that act in one or more capacities as diluents,binders, lubricants, glidants, colorants or flavoring agents. The matrixmay be made by any pharmaceutically acceptable technique that achievesuniform blending, e.g., dry blending, wet granulation, compaction, andfluid bed granulation.

Suitable diluents include pharmaceutically acceptable inert fillers,such as one or more of microcrystalline cellulose, lactose, dibasiccalcium phosphate, mannitol, starch, sorbitol, sucrose, dextrose,maltodextrin and mixtures thereof.

Suitable binders may include one or more of polyvinyl pyrrolidone,lactose, starches, gums, waxes, gelatin, polymers and mixtures thereof.

Suitable lubricants include one or more of colloidal silicon dioxide,talc, stearic acid, magnesium stearate, magnesium silicate,polyethylene, sodium benzoate, sodium lauryl sulphate, fumaric acid,zinc stearate, paraffin, and mixtures thereof.

Suitable glidants include, for example, one or more of talc andcolloidal silicon dioxide.

The matrix formed can be compressed to form tablets. Alternatively, thematrix can be formulated as a plurality of discrete, or aggregated,particles, pellets, beads or granules.

The inert core or seeds may be hydro soluble, such as sucrose, lactose,maltodextrin and the like, or hydro insoluble, such as microcrystallinecellulose, partially pregelatinized starch, dicalcium phosphate and thelike. The biguanide and rate-controlling polymer can be coated as asingle layer or as separate layers onto these inert cores; granulatedwith the inert cores; or mixed with inert cores, extruded, andspheronized to form pellets.

The coating may be applied to the inert/active core using a conventionalcoating pan, a spray coater, a rotating perforated pan, or an automatedsystem, such as centrifugal fluidized granulator, a fluidized bedprocess, or any other suitably automated coating equipment.

The extended-release core that contains biguanide may optionally becoated to seal the core. The coated active cores may be dried underconditions effective for drying, e.g., in an oven or by means of gas ina fluidized bed.

Finally, these beads/pellets may be filled into capsules or compressedto form the tablets. The capsule dosage form may include a plurality ofpellets, granules, or beads, or a single, compressed tablet that releasethe biguanide over an extended period of time.

The sulfonylurea as used herein is intended to include, but is notlimited to, glipizide, glimepiride, glibornuride, glyburide,glisoxepide, gliclazide, acetohexamide, chlorpropamide, tolazamide,tolbutamide, and others, and other medicinally active andpharmaceutically acceptable forms from the sulfonylurea class ofcompounds, including their salts, solvates, hydrates, polymorphs,complexes and other such products. For example, suitable sulfonylureasfor use in the present invention are described in U.S. Pat. Nos.5,674,900 and 4,708,868, both of which are incorporated herein byreference in their entirety. In particular, the sulfonylurea used may beglimepiride. The daily effective dose of glimepiride may range from 1 mgto 10 mg and, in particular, the dose may be a single dose of about 2 mgto about 4 mg. The sulfonylurea may be present in an amount from about0.05% to about 10% by weight of the total composition.

A sulfonylurea can be incorporated into the dosage form as an immediaterelease component in a variety of ways. For example, it can beincorporated into an exterior coating for a tablet from which itreleases substantially immediately upon ingestion. Such a coating cansimilarly be applied to each of the particles that form amultiparticulate dosage form of, for example, granules or beads. If thedosage form is to be a capsule, the sulfonylurea can be contained in asingle pellet inside the capsule from which it releases substantiallyimmediately once the capsule shell dissolves. Alternatively, thesulfonylurea can be contained in several smaller pellets, be present asimmediate release particles, or be present as an immediate release layerover the extended release cores or beads. Any conventional method may beused to prepare the layer of sulfonylurea. Conventional pharmaceuticallyacceptable excipients may be incorporated into this layer. Theseexcipients may include one or more of diluents, binders, and lubricants.

The sulfonylurea coating composition may include one or morewater-soluble polymers, such as polyvinyl pyrrolidine, hydroxypropylcellulose, polyvinyl alcohol, hydroxypropyl methylcellulose and thelike. The polymer may be applied as a solution in an organic solvent oras an aqueous dispersion. The solvent may be one or more of water;alcohols, such as ethyl alcohols or isopropyl alcohol; ketones, such asacetone or ethylmethyl ketone; and chlorinated hydrocarbons, such asdichloroethane and trichloroethane. The coating composition also mayinclude one or more of plasticizers, opacifiers, and colorants. Anyconventional coating equipment may be employed to facilitate coating,including a centrifugal fluidized bed coating apparatus, a pan coatingapparatus, or a fluidized bed granulating coating apparatus.

Due to poor dispersibility in solvents, the film-coating compositionthat includes the sulfonylurea includes a wetting agent. Suitablewetting agents include hydrophilic and hydrophobic surfactants.Hydrophilic surfactants may include one or more of hydrophilic non-ionicsurfactants, hydrophilic ionic surfactants, and combinations thereof.

Non-ionic surfactants may be selected from one or more ofalkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; caprylocaproyl macrogolglycerides, polyoxyethylenealkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fattyacid esters; polyethylene glycol glycerol fatty acid esters;polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fattyacid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction products ofpolyols and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.

Ionic surfactants may be selected from one or more of alkyl ammoniumsalts; bile acids and salts, analogues, and derivatives thereof; fattyacid derivatives of amino acids, oligopeptides, and polypeptides;glyceride derivatives of amino acids, oligopeptides, and polypeptides;acyl lactylates; monoacetylated tartaric acid esters of monoglycerides,monoacetylated tartaric acid esters of diglycerides, diacetylatedtartaric acid esters of monoglycerides, diacetylated tartaric acidesters of diglycerides; succinylated monoglycerides; citric acid estersof monoglycerides; citric acid esters of diglycerides; alginate salts;propylene glycol alginate; lecithins and hydrogenated lecithins;lysolecithin and hydrogenated lysolecithins; lysophospholipids andderivatives thereof; phospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; and mixturesthereof.

Hydrophobic surfactants may be selected from one or more of alcohols;polyoxyethylene alkylethers; fatty acids; glycerol fatty acidmonoesters; glycerol fatty acid diesters; acetylated glycerol fatty acidmonoesters; acetylated glycerol fatty acid diesters, lower alcohol fattyacid esters; polyethylene glycol fatty acid esters; polyethylene glycolglycerol fatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of monoglycerides;lactic acid derivatives of diglycerides; propylene glycol diglycerides;sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers, polyethyleneglycolsas esters or ethers, polyethoxylated castor oil; polyethoxylatedhydrogenated castor oil, polyethoxylated fatty acid from castor oil orpolyethoxylated fatty acid from castor oil or polyethoxylated fatty acidfrom hydrogenated castor oil.

The sulfonylurea and the one or more wetting agents are present in thepharmaceutical composition in a weight ratio ranging from about 10:1 toabout 1:25.

One embodiment is a bilayered dosage form that includes the combinationof a biguanide and a sulfonylurea. The term ‘bilayered’ as used hereinencompasses solid dosage forms in which there are two separate druglayers with only one surface in contact with each other. These may beprepared by compressing additional granulation on a previouslycompressed granulation or alternatively by feeding previously compressedtablets into a machine and compressing another granulation layer aroundthe preformed tablets.

Another embodiment includes providing a seal coat of hydrophilicpolymers between the extended-release and immediate-release layers.

Other embodiments include additional or alternative modifications thatinvolve coating the tablet with the polymer in order to modify therelease of the drug. The solid dosage forms may be optionally coatedwith non-functional coatings well known in the art, or with coatingsthat further modify the release of the drug from the said dosage form.All such modifications as may be done and understood by those who areskilled in the art are within the scope of the present invention. Forexample, one such modification includes making the compositions into alayered tablet such that the composition provides extended release ofmore than one therapeutic agent, or extended release of one of thetherapeutic agents and immediate or delayed release of the othertherapeutic agent(s).

EXAMPLE 1

INGREDIENTS Mg/tablet CORE Metformin hydrochloride 500 Microcrystallinecellulose 245 Sodium carboxymethyl cellulose 150 Purified water q.s.Hydroxypropyl methylcellulose 100 Magnesium stearate 5 SEALHydroxypropyl methylcellulose E5 15.6 COAT Polyethylene glycol 4000 4.8Titanium dioxide 2.4 Talc 1.2 Purified water q.s. ACTIVE Glimepiride(20% extra to compensate for losses) 1.2 COAT Caprylocaporylmacrogolglycerides 14.4 Hydroxypropyl methylcellulose E5 29.35Polyethylene glycol 4000 8.6 Titanium dioxide 4.3 Talc 2.15 Purifiedwater q.s.Procedure:

-   1. Metformin hydrochloride was milled through a 1 mm screen and    mixed with microcrystalline cellulose and sodium carboxymethyl    cellulose. The blend was sieved through a No. 44 mesh, transferred    to a rapid mixer granulator, and wet granulated with purified water.    The granules were dried in fluid bed dryer, sized through a    multimill, and sifted through a No. 30 mesh.-   2. Hydroxypropyl methylcellulose was separately sifted through a No.    30 mesh and mixed with granules in a low shear mixer. The blend then    was mixed with magnesium stearate and compressed into tablets.-   3. A coating dispersion was prepared by dispersing all of the    ingredients of the seal coat in water. The tablets then were coated    with this dispersion until obtaining a weight build up of 5%.-   4. To prepare the active coat, caprylocaproyl monoglyceride was    dissolved in purified water. To this solution, glimepiride was added    with stirring to form a dispersion. The other ingredients of the    active coat were added with stirring to this dispersion and the    resulting dispersion then was spray-coated upon the tablets obtained    from step 3 until obtaining a weight build up of 10%.

EXAMPLE 2

INGREDIENTS Mg/tablet CORE Metformin hydrochloride 500 Microcrystallinecellulose 245 Sodium carboxymethyl cellulose 150 Hydroxypropylmethylcellulose 100 Magnesium stearate 5 SEAL Hydroxypropylmethylcellulose E5 15.6 COAT Polyethylene glycol 4000 4.8 Titaniumdioxide 2.4 Talc 1.2 Purified water q.s. ACTIVE Glimepiride equivalentto 2 mg (20% extra 2.4 COAT to compensate for losses) Caprylocaporylmacrogolglycerides 14.4 Hydroxypropyl methylcellulose E5 28.15Polyethylene glycol 4000 8.6 Titanium dioxide 4.3 Talc 2.15 Purifiedwater q.s.Procedure:

-   1. Metformin hydrochloride was milled through a 1 mm screen and    mixed with microcrystalline cellulose and sodium carboxymethyl    cellulose. The blend was sieved through a No. 44 mesh.-   2. Hydroxypropyl methylcellulose was separately sifted through a No.    30 mesh and mixed with the blend of step 1 in a low shear mixer. The    blend then was mixed with magnesium stearate, passed through roller    compactor, and then milled again to form granules. These granules    then were compressed into tablets.-   3. A coating dispersion was prepared by dispersing all of the    ingredients of the seal coat in water. The tablets then were coated    with this dispersion until obtaining a weight build up of 5%.-   4. To prepare the active coat, caprylocaproyl monoglyceride was    dissolved in purified water. To this solution, glimepiride was added    with stirring to form a dispersion. The other ingredients of the    active coat were added with stirring to this dispersion. The    resulting dispersion then was spray-coated onto the tablets obtained    from step 3 until obtaining a weight build up of 8.0%.

A comparative dissolution profile was obtained of metforminhydrochloride in the innovator's marketed tablets (Glucophage XR 500 mg)and tablet formulation of Example 2. The dissolution was carried out ina USP Apparatus Type I (basket) at a speed of 100 rpm. The medium was900 ml phosphate buffer at pH 6.8. The data obtained is provided inTable 1. TABLE 1 Comparative dissolution profile of metforminhydrochloride in Glucophage XR 500 mg vs tablets of Example 2 Percent(%) metformin hydrochloride released Time (hrs) Glucophage XR Tablets(Example 2) 0 0 0 1 29 28 4 60 64 8 83 91 12 99 100

From the results of Table 1, it is evident that almost all of the drugis released in twelve hours in both the formulations, thereby showingsubstantially similar dissolution profiles.

A comparative dissolution profile was obtained of glimepiride in theinnovator's marketed tablets (Amaryl 2 mg) and the tablet formulation ofExample 2. The dissolution was carried out in a USP Apparatus Type I ata speed of 100 rpm. The medium was 900 ml phosphate buffer at pH 8. Thedata obtained is provided in Table 2. TABLE 2 Comparative dissolutionprofile of glimepiride in Amaryl 2 mg vs tablets of Example 2 Percent(%) Glimepiride released Time (hrs) Amaryl 2 mg Tablets (Example 2) 0 00 15 95 92 30 98 101 45 98 105

From the results of Table 2, it is evident that more than 90% of thedrug is released in fifteen minutes in both the formulations, therebyshowing substantially similar dissolution profiles.

EXAMPLE 3

INGREDIENTS mg/tablet CORE Metformin hydrochloride 500 Microcrystallinecellulose 245 Sodium carboxymethyl cellulose 150 Hydroxypropylmethylcellulose 100 Magnesium stearate 5 SEAL Hydroxypropylmethylcellulose E5 15.6 COAT Polyethylene glycol 4000 4.8 Titaniumdioxide 2.4 Talc 1.2 Purified water q.s. ACTIVE Glimepiride equivalentto 2 mg (20% extra to 2.4 COAT compensate for losses) Hydroxypropylmethylcellulose E5 37.2 Polyethylene glycol 400 7.2 Titanium dioxide 6.2Talc 12.0 Methylene chloride q.s. Isopropyl alcohol q.s.Procedure:

-   1. Metformin hydrochloride was milled through a 1 mm screen and    mixed with microcrystalline cellulose and sodium carboxymethyl    cellulose. The blend was sieved through a No. 44 mesh.-   2. Hydroxypropyl methylcellulose was separately sifted through a No.    30 mesh and mixed with the blend in a low shear mixer. The blend    then was mixed with magnesium stearate and compressed into tablets.-   3. A coating dispersion was prepared by dispersing all of the    ingredients of the seal coat in water. The tablets were coated with    this dispersion until obtaining a weight build up of 2%.-   4. To prepare the active coat, glimepiride was dissolved in a    methylene chloride:isopropyl alcohol mix (2:1). The other    ingredients of the active coat were added with stirring to this    solution. The resulting dispersion then was spray-coated upon the    tablets obtained from step 3 until obtaining a weight build up of    10%.

While several particular forms of the inventions have been illustratedand described, it will be apparent that various modifications andcombinations of the inventions detailed in the text can be made withoutdeparting from the spirit and scope of the inventions. For example, abilayered tablet that include extended-release biguanide in one layerand immediate-release sulfonylurea in another layer may be preparedaccording to the example given below.

EXAMPLE 4

Preparation of Bilayered Tablets: INGREDIENTS Mg/tablet MetforminMetformin hydrochloride 500 layer Microcrystalline cellulose 245 Sodiumcarboxymethyl cellulose 150 Hydroxypropyl methylcellulose 100 Magnesiumstearate 5 Seal Coat Hydroxypropyl methylcellulose E5 15.6 Polyethyleneglycol 4000 4.8 Titanium dioxide 2.4 Talc 1.2 PiosulfonylureaGlimepiride equivalent to 2 mg 2.4 layer Lactose 143 Microcrystallinecellulose 20 Sodium starch glycolate 6.0 Polyvinylpyrrolidone 2.5Magnesium stearate 1.0 Purified water q.s.Procedure:

-   1. Metformin hydrochloride was milled and mixed with    microcrystalline cellulose and sodium carboxymethyl cellulose. The    blend was sieved.-   2. Hydroxypropyl methylcellulose was separately sifted and mixed    with the blend of step 1 in a low shear mixer. The blend then was    mixed with magnesium stearate and passed through a roller compactor    and then milled again to form granules.-   3. Glimepiride, lactose, microcrystalline cellulose and sodium    starch glycolate were blended and granulated with a solution of    polyvinylpyrrolidone in purified water.-   4. The wet mass of step 3 was granulated, dried, and sifted.-   5. The lubricated granules of metformin and glimepiride were    compressed into bilayer tablets using a rotary compression machine.

Further, it is contemplated that any single feature or any combinationof optional features of the inventive variations described herein may bespecifically excluded from the claimed invention and be so described asa negative limitation. Accordingly, it is not intended that theinvention be limited, except as by the appended claims.

1. A solid pharmaceutical dosage form for oral administration, thedosage form comprising: an extended release layer comprising abiguanide; and an immediate release layer comprising a sulfonylurea. 2.The dosage form of claim 1, wherein the biguanide comprises one or moreof metformin, phenformin, and buformin.
 3. The dosage form of claim 1,wherein the biguanide is metformin.
 4. The dosage form of claim 1,wherein the sulfonylurea comprises one or more of glipizide,glimepiride, glibornuride, glyburide, glisoxepide, gliclazide,acetohexamide, chlorpropamide, tolazamide and tolbutamide.
 5. The dosageform of clam 1, wherein the sulfonylurea is glimepiride.
 6. The dosageform of claim 1, wherein after oral administration the biguanide isreleased over a period of about 4 to about 36 hours.
 7. The dosage formof claim 6, wherein the biguanide is released over a period of about 8to about 24 hours.
 8. (canceled)
 9. (canceled)
 10. (canceled)
 11. Thedosage form of claim 1, wherein the extended release layer comprises amatrix.
 12. The dosage form of claim 11, wherein the matrix comprises auniform mixture of the biguanide and one or more rate controllingpolymers.
 13. (canceled)
 14. The dosage form of claim 11, wherein thematrix further comprises one or more pharmaceutically acceptableexcipients.
 15. The dosage form of claim 14, wherein thepharmaceutically acceptable excipients comprise one or more of diluents,lubricants, disintegrants, binders, glidants, coloring agents, andflavoring agents.
 16. The dosage form of claim 1, wherein the biguanideis layered onto a pharmaceutically inert core or seed.
 17. The dosageform of claim 16, wherein the inert core or seed is hydrosoluble orhydroinsoluble.
 18. The dosage form of claim 1, wherein the immediaterelease outer layer further comprises film-forming polymers andoptionally other pharmaceutically acceptable excipients.
 19. The dosageform of claim 18, wherein the film-forming polymers are water-solublepolymers.
 20. The dosage form of claim 18, wherein the pharmaceuticallyacceptable excipients comprise one or more of plasticizers, opacifiersand colorants.
 21. The dosage form of claim 1, further comprising one ormore of glitazones, insulin, alpha-glucosidase inhibitors, meglitinides,fibrates, statins, squalene synthesis inhibitors andangiotensin-converting enzyme inhibitors.
 22. The dosage form of claim1, further comprising a wetting agent in the immediate release layer,wherein the immediate release layer comprises a sulfonylurea and thewetting agent in a weight ratio ranging from about 10:1 to about 1:25.23. The dosage form of claim 22, wherein the wetting agent comprises oneor more of hydrophilic and hydrophobic surfactants.
 24. The dosage formof claim 23, wherein the hydrophilic surfactants comprises one or moreof non-ionic surfactants, ionic surfactants or mixtures thereof. 25.(canceled)
 26. (canceled)
 27. (canceled)
 28. The dosage form of claim 1,wherein the extended release layer comprises a core and the immediaterelease layer covers at least a portion of the core.
 29. The dosage formof claim 1, wherein the dosage form comprises a bilayered dosage form.30. A process for preparing a solid, orally administered pharmaceuticaldosage form of an extended release core of a biguanide and an immediaterelease layer of a sulfonylurea, the process comprising: a. dispersingthe biguanide in a solid matrix to form a core having a surface; and b.layering the immediate release layer of the sulfonylurea on the surfaceof the core.
 31. The process of claim 30, wherein layering the immediaterelease layer further comprises layering one or more wetting agents. 32.The process of claim 31, wherein the sulfonylurea and the one or morewetting agents are present in the immediate release layer in a weightratio ranging from about 10:1 to about 1:25.
 33. (canceled) 34.(canceled)
 35. (canceled)
 36. (canceled)
 37. (canceled)
 38. (canceled)39. (canceled)
 40. (canceled)
 41. (canceled)
 42. The process of claim30, wherein after oral administration the biguanide is released over aperiod of about 4 to about 36 hours.
 43. The process of claim 42,wherein the biguanide is released over a period of about 8 to about 24hours.
 44. (canceled)
 45. (canceled)
 46. (canceled)
 47. (canceled) 48.(canceled)
 49. (canceled)
 50. (canceled)
 51. (canceled)
 52. The processof claim 30, wherein the biguanide is layered onto pharmaceuticallyinert core or seeds.
 53. (canceled)
 54. The process of claim 30, whereinthe immediate release outer layer further comprises film-formingpolymers and optionally other pharmaceutically acceptable excipients.55. (canceled)
 56. (canceled)
 57. The process of claim 30, furthercomprising placing a seal-coat over the core, wherein the seal-coatcomprises hydrophilic polymers.
 58. A process for preparing a bilayered,solid, orally administered pharmaceutical dosage form of a biguanide anda sulfonylurea, the process comprising: a. dispersing the biguanide inan extended release carrier base material; b. separately dispersing thesulfonylurea in an immediate release carrier base material; and c.compressing the materials of step a and step b to form the bilayereddosage form.
 59. The process of claim 58, wherein the immediate releasecarrier base material further comprises one or more wetting agentsbefore or after dispersing the sulfonylurea.
 60. The process of claim59, wherein the sulfonylurea and the one or more wetting agents arepresent in a weight ratio ranging from about 10:1 to about 1:25. 61.(canceled)
 62. (canceled)
 63. (canceled)
 64. (canceled)
 65. (canceled)66. (canceled)
 67. (canceled)
 68. (canceled)
 69. (canceled) 70.(canceled)
 71. (canceled)
 72. (canceled)
 73. (canceled)
 74. (canceled)75. (canceled)
 76. (canceled)
 77. (canceled)
 78. (canceled) 79.(canceled)
 80. The process of claim 58, wherein the biguanide is layeredonto pharmaceutically inert core or seeds.
 81. The process of claim 80,wherein the inert core or seeds are hydrosoluble or hydroinsoluble. 82.(canceled)
 83. (canceled)
 84. (canceled)
 85. (canceled)
 86. A method oftreating non-insulin dependent diabetes mellitus in a patient in needthereof, the method comprising administering a solid, pharmaceuticaldosage form of the combination of a biguanide and a sulfonylurea,wherein the dosage form provides extended-release of the biguanide andimmediate release of the sulfonylurea.
 87. The method of claim 86,wherein the biguanide comprises one or more of metformin, phenformin,and buformin.
 88. The method of claim 86, wherein the biguanide ismetformin.
 89. The method of claim 86, wherein the sulfonylureacomprises one or more of glipizide, glimepiride, glibornuride,glyburide, glisoxepide, gliclazide, acetohexamide, chlorpropamide,tolazamide and tolbutamide.
 90. The method of clam 86, wherein thesulfonylurea is glimepiride.
 91. (canceled)
 92. (canceled) 93.(canceled)
 94. The method of claim 86, wherein the dosage form furthercomprises one or more of glitazones, insulin, alpha-glucosidaseinhibitors, meglitinides, fibrates, statins, squalene synthesisinhibitors and angiotensin-converting enzyme inhibitors.